Peptidyl prodrugs that resist P-glycoprotein mediated drug efflux
Inventors
Mitra, Ashim K. • Majumdar, Soumyajit • Jain, Ritesh • Nashed, Yasser
Assignees
University of Missouri System • University of Missouri St Louis
Publication Number
US-7214664-B2
Publication Date
2007-05-08
Expiration Date
2025-11-22
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Dipeptide, and tripeptide and tetrapeptide ester derivatives of bioactive agents are provided wherein the parent agents are substrates effluxed by the P-gp transporter. The derivatives are useful in treating the same condition as the bioactive agent. Also disclosed is a method for preparing a bioactive agent for targeted delivery by nutrient or peptide transporters comprising linking the agent to one or more groups of the formula —X—Y(n)-Z(n′)-Z′(n″)-R; wherein each X, Y, Z, and Z′ is independently Met, Val, Thr, Tyr, Trp, Ser, Ala or Gly; R is independently H or an amino-protecting group; n=1, and each, n′, or n″ is independently 0 or 1.
Core Innovation
The invention provides novel dipeptide, tripeptide, and tetrapeptide ester derivatives of bioactive agents—specifically those that are substrates effluxed by the P-glycoprotein (P-gp) transporter—such that the resulting derivatives are not recognized by P-gp, but can instead be taken up by nutrient or peptide transporters. By linking these drugs to amino acid or small peptide groups comprising Met, Val, Thr, Tyr, Trp, Ser, Ala, or Gly, the derivatives can bypass the P-gp mediated efflux mechanism.
The problem addressed by this invention is the limited bioavailability and therapeutic effectiveness of various drugs that are substrates of P-gp, which aggressively expels them from cells, including in sanctuary sites like the brain, intestines, and tumor tissues. This efflux restricts drug concentrations in target tissues, impairs treatment efficacy, and contributes to multidrug resistance, especially in chemotherapy and anti-HIV therapy. Traditional chemical inhibitors of P-gp to counteract this problem are limited by toxicity concerns.
The core innovation involves designing prodrugs of P-gp substrate drugs, attaching them to specific amino acid or oligopeptide moieties to convert them into substrates of nutrient and peptide influx transporters while reducing or eliminating their recognition by the P-gp efflux transporter. This enhances delivery to cells and increases drug levels in sanctuary sites, as demonstrated with examples such as val-quinidine, val-val-quinidine, and peptide derivatives of saquinavir. These prodrugs can be hydrolyzed intracellularly to release the active drug at the target site.
Claims Coverage
There are two key independent inventive features in the patent claims, centering on specific compound derivatives and pharmaceutical compositions.
Peptide derivative compounds that are not recognized by P-gp
Compounds of formula (I), where a bioactive agent that is a P-glycoprotein substrate is linked to one or more groups of —X—Y(n)-Z(n′)-Z′(n″)-R, wherein each of X, Y, Z, and Z′ is independently Met, Val, Thr, Tyr, Trp, Ser, Ala, or Gly; R is H or an amino-protecting group; and each n, n′, or n″ is independently 0 or 1. These include dipeptide, tripeptide, and tetrapeptide esters of the bioactive agents, with the stipulation that the resulting derivatives are not recognized by P-gp as a substrate.
Pharmaceutical compositions comprising peptide derivatives with same therapeutic purpose as free drug
A pharmaceutical composition that includes an effective amount of a compound as described above, in combination with a pharmaceutically acceptable carrier, where the effective amount is based on the quantity of free drug released from the compound. The compound within the composition is effective for the same purpose as the free drug.
The independent claims broadly cover both the design of specific amino acid/peptidyl derivatives of P-gp substrate drugs that avoid P-gp mediated efflux and the formulation of pharmaceutical compositions containing these derivatives to improve drug bioavailability and therapeutic use.
Stated Advantages
Microsomal metabolism of the free bioactive agent is reduced due to derivatization.
Protein binding is reduced when a polar peptide is used in the derivatization.
The compounds are more water soluble than the free drugs if polar or ionic molecules are used in the derivatization.
The derivatives are not recognized by P-gp as substrates, thus circumventing P-gp mediated drug efflux.
Higher bioavailability of the free drug at targeted sites and in sanctuary sites such as the brain, spinal cord, intestines, kidneys, bone-marrow, and lungs.
The derivatives can be targeted to membrane nutrient transporters, enhancing cellular internalization.
Prodrugs are hydrolyzed intracellularly to release the active drug at the site of action.
Potential for increased absorption and reduced dose requirements for poorly absorbed drugs.
Strategy circumvents toxicity issues associated with chemical P-gp inhibitors by using transporter-targeted prodrug design.
Documented Applications
Use for drug treatment with anticancer drugs, anti-HIV drugs (including HIV protease inhibitors), calcium channel blockers, and other P-gp substrate drugs with limited bioavailability due to efflux transporters.
Drug treatment of viral diseases wherein the virus persists in sanctuary sites such as the brain, lung, or bone-marrow.
Delivery of drugs across biological barriers with dense P-gp expression, such as the blood-brain barrier, intestines, kidneys, bone-marrow, and lungs.
Enhancement of ocular drug delivery and bioavailability in the cornea, demonstrated with in vivo rabbit studies.
Oral, parenteral, topical, and other systemic pharmaceutical formulations for human and animal patients.
Interested in licensing this patent?